This invention relates generally to nitrogen containing heterobicycles, which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
WO94/20460 describes angiotensin II compounds of the following formula: 
wherein X can be a number of substituents and Het can be a nitrogen-containing heterobicycle. However, WO94/20460 does not suggest Factor Xa inhibition or exemplify compounds like those of the present invention.
WO96/12720 describes phosphodiesterase type IV and TNF production inhibitors of the following formula: 
wherein X can be oxygen and R2 and R3 can a number of substituents including heterocycle, heterocycloalkyl, and phenyl. However, the presently claimed compounds do not correspond to the compounds of WO96/12720. Furthermore, WO96/12720 does not suggest Factor Xa inhibition.
WO98/52948 describes inhibitors of ceramide-mediated signal transduction. One of the types of inhibitors described is of the following formula: 
wherein Y1 can be Nxe2x80x94R6, R6 can be unsubstituted aryl-alkyl or unsubstituted heterocyclic-alkyl and R1 can be a substituted aryl group. WO98/52948 does not mention factor Xa inhibition or show compounds like those of the present invention.
U.S. Pat. Nos. 3,365,459 and 3,340,269 illustrates anti-inflammatory inhibitors of the following formula: 
wherein A is 2-3 carbon atoms, X can be O, and R1 and R3 can be substituted or unsubstituted aromatic groups. Neither of these patents, however, exemplify compounds of the present invention.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
Accordingly, one object of the present invention is to provide novel nitrogen containing heterobicycles that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel bicyclic compounds for use in therapy.
It is another object of the present invention to provide the use of novel bicyclic compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that the presently claimed bicyclic compounds, or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.
[1] Thus, in a first embodiment, the present invention provides a novel compound selected from the group: 
or a stereoisomer or pharmaceutically acceptable salt thereof wherein compounds of the above formulas are substituted with 0-2 R3;
G is a group of formula I or II: 
xe2x80x83ring D is selected from xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94CH2Nxe2x95x90CHxe2x80x94, xe2x80x94CH2CH2Nxe2x95x90CHxe2x80x94, and a 5-6 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S, provided that from 0-1 O and S atoms are present;
ring D, when present, is substituted with 0-2 R;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substituted with 0-1 R;
R is selected from Cl, F, Br, I, OH, C1-3 alkoxy, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), and CH2CH2N(C1-3 alkyl)2;
alternatively, ring D is absent;
when ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with Rxe2x80x3 and Rxe2x80x2;
Rxe2x80x3 is selected from F, Cl, Br, I, OH, C1-3 alkoxy, CN, C(xe2x95x90NR8)NR7R9, NHC(xe2x95x90NR8)NR7R9, NR8CH(xe2x95x90NR7), C(O)NR7R8, (CR8R9)tNR7R8, SH, C1-3 alkyl-S, S(O)R3b, S(O)2R3a, S(O)2NR2R2a, and OCF3;
Rxe2x80x2 is selected from H, F, Cl, Br, I, SR3, CO2R3, NO2, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
alternatively, Rxe2x80x3 and Rxe2x80x2 combine to form methylenedioxy or ethylenedioxy;
Z is N or CR1a;
Z1 is S, O, or NR3;
Z2 is selected from H, C1-4 alkyl, phenyl, benzyl, C(O)R3, and S(O)pR3c;
R1a is selected from H, xe2x80x94(CH2)rxe2x80x94R1xe2x80x2, xe2x80x94CHxe2x95x90CHxe2x80x94R1xe2x80x2, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, NH(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
R1xe2x80x2 is selected from H, C1-3 alkyl, F, Cl, Br, I, xe2x80x94CN, xe2x80x94CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, C(xe2x95x90NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)R3, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4a, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R1xe2x80x3 is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, a C3-6 carbocyclic-CH2- residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R4, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
B is selected from:
Xxe2x80x94Y, C(xe2x95x90NR2)NR2R2a, NR2C(xe2x95x90NR2)NR2R2a,
C3-10 carbocyclic residue substituted with 0-2 R4a, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
X is selected from C1-4 alkylene, xe2x80x94CR2(CR2R2b)(CH2)txe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR1xe2x80x3)xe2x80x94, xe2x80x94CR2(NR1xe2x80x3R2)xe2x80x94, xe2x80x94CR2(OR2)xe2x80x94, xe2x80x94CR2(SR2)xe2x80x94, xe2x80x94C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O), xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR2R2axe2x80x94, xe2x80x94CR2R2aS(O)pxe2x80x94, xe2x80x94S(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2xe2x80x94, xe2x80x94NR2S(O)2CR2R2axe2x80x94, xe2x80x94CR2R2aS(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2NR2xe2x80x94, xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, xe2x80x94NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)Oxe2x80x94, xe2x80x94OC(O)NR2xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2CR2R2axe2x80x94, xe2x80x94CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and xe2x80x94OCR2R2axe2x80x94;
Y is selected from:
CH2NR2R2a;
CH2CH2NR2R2a;
C3-10 carbocyclic residue substituted with 0-2 R4a, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, C(xe2x95x90NR2)NR2R2a, C(xe2x95x90NS(O)2R5)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, C(O)NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, N(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R4a, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, (CH2)rxe2x80x94F, (CH2)rxe2x80x94Br, (CH2)rxe2x80x94Cl, Cl, Br, F, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, (CH2)rNxe2x95x90CHOR3, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, C(xe2x95x90NR2)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, C(O)NHSO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;
R4b at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, C(xe2x95x90NR3)NR3R3a, NR3C(xe2x95x90NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)pxe2x80x94C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a,(CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6 10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
alternatively, R7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
n, at each occurrence, is selected from 0, 1, 2, and 3;
m, at each occurrence, is selected from 0, 1, and 2;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
s, at each occurrence, is selected from 0, 1, and 2; and,
t, at each occurrence, is selected from 0, 1, 2, and 3.
[2] In a preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from the group: 
wherein compounds of the above formulas are substituted with 0-2 R3;
G is selected from the group: 
xe2x80x83A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
B is selected from: H, Y, and Xxe2x80x94Y;
X is selected from C1-4 alkylene, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR)xe2x80x94, xe2x80x94CR2(NR2R2a)xe2x80x94, xe2x80x94C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O), xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, xe2x80x94NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2CR2R2axe2x80x94, xe2x80x94CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and xe2x80x94OCR2R2axe2x80x94;
Y is CH2NR2R2a or CH2CH2NR2R2a;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems that are substituted with 0-2 R4a;
cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
alternatively, Y is selected from the following bicyclic heteroaryl ring systems: 
xe2x80x83K is selected from O, S, NH, and N; and,
s is 0.
[3] In a more preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from the group: 
wherein compounds of the above formulas are substituted with 0-2 R3;
G is selected from the group: 
[4] In an even more preferred embodiment, the present invention provides a novel compound, wherein:
G is selected from: 
[5] In a still more preferred embodiment, the present invention provides a novel compound, wherein;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and,
B is selected from Xxe2x80x94Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
R2, at each occurrence, is selected from H, CH3, CH2CH3, cyclopropylmethyl, cyclobutyl, and cyclopentyl;
R2a, at each occurrence, is H or CH3;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form pyrrolidine substituted with 0-2 R4b;
R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3;
R4a is selected from C1-4 alkyl, CF3, (CH2)rOR2, (CH2)rNR2R2a, S(O)pR5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;
R4b, at each occurrence, is selected from H, CH3, and OH;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
X is CH2 or C(O);
Y is selected from pyrrolidino and morpholino; and,
r, at each occurrence, is selected from 0, 1, and 2.
[6] In a further preferred embodiment, the present invention provides a novel compound, wherein;
A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,
B is selected from the group: 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl, 1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 2-(dimethylaminomethyl)-1-imidazolyl, 2-(N-(cyclopropylmethyl)aminomethyl)phenyl, 2-(N-(cyclobutyl)aminomethyl)phenyl, 2-(N-(cyclopentyl)aminomethyl)phenyl, and 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl.
[7] In an even further preferred embodiment, the present invention provides a novel compound selected from:
1-[4-Methoxyphenyl]-3-cyano-6-[2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4-dihydropyrazolo-[4,3-d]-pyrimidine-5,7-dione;
1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-6-[2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(methoxycarbonyl)-6-[2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-6-[2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one-3-carboxylic acid;
1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-cyano-6-[2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(aminomethyl)-6-[2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[4-(2-methylimidazol-1xe2x80x2-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[4-(2-methylimidazol-1xe2x80x2-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2 xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-cyano-6-[2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2-fluoro-4-(2-dimethylaminomethylimidazol-1xe2x80x2-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[2-Aminomethylphenyl]-3-(ethoxycarbonyl)-6-[2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminoiminomethylphenyl]-3-methyl-6-[2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[2-Aminomethylphenyl]-3-methyl-6-[2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[4-Methoxyphenyl]-3-cyano-6-[2xe2x80x2-N,N-dimethylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-cyano-5-methyl-6-[2xe2x80x2-N,N-dimethylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[2-Aminomethylphenyl]-3-cyano-6-[2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-4-methyl-6-[2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[3,4-d]-pyridazin-7-one,
1-[3-Aminobenzisoxazol-5 xe2x80x2-yl]-3-trifluoromethyl-6-[4-(1-methylimidazol-2xe2x80x2-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2xe2x80x2-hydroxymethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(ethoxycarbonyl)-6-[2xe2x80x2-N-pyrrolidinylmethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-1-(aminocarbony)-6-[2xe2x80x2-N-pyrrolidinylmethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(aminocarbonyl)-6-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinylmethyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-(N-formylaminomethyl)-6-[2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-(ethoxycarbonyl)-6-[2xe2x80x2-hydroxymethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5 xe2x80x2-yl]-3-(ethoxycarbonyl)-6-[2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[3-Aminobenzisoxazol-5 xe2x80x2-yl]-3-trifluoromethyl-7-[2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[3-Aminobenzisoxazol-5 xe2x80x2-yl]-3-trifluoromethyl-7-[2xe2x80x2-N-dimethylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-7-[2xe2x80x2-N-isopropylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-7-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-7-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-7-[2xe2x80x2-N-pyrrolidinylmethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-7-[2xe2x80x2-N-dimethylaminomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-7-[2xe2x80x2-N-isopropylaminomethy-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-(2-dimethylaminomethylimidazol-1xe2x80x2-yl)-3-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-(imidazol-1xe2x80x2-yl)-3-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[2-Aminomethylphenyl]-3-trifluoromethyl-7-[2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]-azepin-8-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-(3-(S)-hydroxy-N-pyrrolidinyl)methyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-N-isopropylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-N,N-dimethylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5 xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydro-7H-pyrazolo-[3 ,4-c]-pyridin-7-one;
1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2xe2x80x2-N,N-dimethylaminomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[2-Aminomethylphenyl]-3-trifluoromethyl-6-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-dimethylaminomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1- [3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-isopropylaminomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-N-(2-methylimidazol-1-yl)methyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-N-pyrrolidinomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-oximinomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-6-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro-[1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminomethylphenyl]-3-trifluoromethyl-6-[2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[4-Methoxyphenyl]-3-[(imidazol-1-yl)methyl]-5-methyl-6-[(2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-[(tetrazol-1-yl)methyl]-5-methyl-6-[(2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[4-Methoxyphenyl]-3-[(tetrazol-2-yl)methyl]-5-methyl-6-[(2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl)]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3,5-dimethyl-6-[2xe2x80x2-N-dimethylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-N,N-dimethylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-N-isopropylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[4-(4,5-dihydroimidazol-1xe2x80x2-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-N-(cyclopropylmethyl)aminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[2xe2x80x2-(N-methyl-N-isopropyl)aminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-di-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3,5-dimethyl-6-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-N,N-dimethylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-N,N-dimethylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-(3-(S)-hydroxy-N-pyrrolidinyl)methyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-N-(pyrrolindinyl)methyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-N-(morpholino)methyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[2xe2x80x2-N,N-dimethylaminomethyl-[1,1xe2x80x2]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-7-[(3xe2x80x2-N-dimethylaminomethyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-7-[(3xe2x80x2-N-pyrrolidinylmethyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(3xe2x80x2-N-pyrrolidinylmethyl)-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(3xe2x80x2-N-dimethylaminomethyl)-[1,1xe2x80x2]-biphen-4-yl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[4-benzimidazol-1xe2x80x2-yl-3-fluorophenyl]-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one;
1-[3-Aminobenzisoxazo-5xe2x80x2-yl]-3-trifluoromethyl-7-[(2xe2x80x2-N-pyrrolidinylmethyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;
1-[3-Aminobenzisoxazo-5xe2x80x2-yl]-3-trifluoromethyl-7-[(2xe2x80x2-N-dimethylaminomethyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;
1-[3-Aminobenzisoxazo-5xe2x80x2-yl]-3-trifluoromethyl-7-[(2xe2x80x2-N-(R)-3-hydroxypyrrolidinylmethyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;
1-[3-Aminobenzisoxazo-5xe2x80x2-yl]-3-trifluoromethyl-7-[(2xe2x80x2-N-(R)-3-hydroxypyrrolidinylmethyl)-[1,1xe2x80x2]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;
1-[3-Aminobenzisoxazo-5xe2x80x2-yl]-3-trifluoromethyl-7-[(2xe2x80x2-N-dimethylaminomethyl)-[1,1xe2x80x2]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(2xe2x88x9d-N-pyrrolidinylmethyl)-[1,1xe2x80x2]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-7-[(2xe2x80x2-N,N-dimethylaminomethyl)-[1,1xe2x80x2]-biphen-4-yl]-6,7-dihydropyrazolo-[3,4-c]azepin-8-one;
1-[4-Methoxyphenyl]-3-trifluoromethyl-6-[(4-aminomethyl)phenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]pyridin-7-one;
1-[3-Aminomethylphenyl]-3-methyl-6-[(2xe2x80x2-N-((3-(S)-hydroxy)pyrrolidinyl) methyl-[1,1xe2x80x2]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo-[3,4-c]-pyridin-7-one;
1-[3-Aminomethylphenyl]-3-methyl-6-[(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[(3-fluoro-2xe2x80x2-N-(3(S)-hydroxy)pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[(3-fluoro-2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl)]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;
1-[1-Aminoisoquinolin-7xe2x80x2-yl]-3-trifluoromethyl-6-[4-(2-methylimidazol-1xe2x80x2-yl)phenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one; 1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[4-(2-methylimidazol-1xe2x80x2-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[4-(2-(dimethylaminomethyl)imidazol-1xe2x80x2-yl)-2-fluorophenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one;
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-trifluoromethyl-6-[4-(2-(dimethylaminomethyl)imidazol-1xe2x80x2-yl)phenyl]-1,6-dihydropyrazolo-[4,3-d]-pyrimidin-7-one; and,
1-[3-Aminobenzisoxazol-5xe2x80x2-yl]-3-methyl-6-[4-(2-(dimethylaminomethyl)imidazol-1xe2x80x2-yl)-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one;
or a pharmaceutically acceptable salt form thereof.
[8] Thus, in another embodiment, the present invention provides a novel compound selected from the group: 
or a stereoisomer or pharmaceutically acceptable salt thereof wherein compounds of the above formulas are substituted with 0-2 R3;
G is a group of formula I or II: 
xe2x80x83ring D is selected from xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94CH2Nxe2x95x90CHxe2x80x94, xe2x80x94CH2CH2Nxe2x95x90CHxe2x80x94, and a 5-6 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S, provided that from 0-1 O and S atoms are present;
ring D, when present, is substituted with 0-2 R;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substituted with 0-1 R;
R is selected from Cl, F, Br, I, OH, C1-3 alkoxy, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), and CH2CH2N(C1-3 alkyl)2;
alternatively, ring D is absent;
when ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with Rxe2x80x3 and Rxe2x80x2;
Rxe2x80x3 is selected from F, Cl, Br, I, OH, C1-3 alkoxy, CN, C(xe2x95x90NR8)NR7R9, NHC(xe2x95x90NR8)NR7R9, NR8CH(xe2x95x90NR7), C(O)NR7R8, (CR8R9)tNR7R8, SH, C1-3 alkyl-S, S(O)R3b, S(O)2R3a, S(O)2NR2R2a, and OCF3;
Rxe2x80x2 is selected from H, F, Cl, Br, I, SR3, CO2R3, NO2, (CH2)tOR3, C1-4 alkyl, OCF3,CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
alternatively, Rxe2x80x3 and Rxe2x80x2 combine to form methylenedioxy or ethylenedioxy;
Z is N or CR1a;
Z1 is S, O, or NR3;
Z2 is selected from H, C1-4 alkyl, phenyl, benzyl, C(O)R3, and S(O)pR3c;
R1a is selected from H, xe2x80x94(CH2)rxe2x80x94R1xe2x80x2, xe2x80x94CHxe2x95x90CHxe2x80x94R1xe2x80x2, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, NH(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
R1xe2x80x2 is selected from H, C1-3 alkyl, F, Cl, Br, I, xe2x80x94CN, xe2x80x94CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, C(xe2x95x90NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)R3, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4a, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R1xe2x80x3 is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, a C3-6 carbocyclic-CH2-residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R4, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
B is selected from:
Xxe2x80x94Y, NR2R2a, C(xe2x95x90NR2)NR2R2a, NR2C(xe2x95x90NR2)NR2R2a,
C3-10 carbocyclic residue substituted with 0-2 R4a and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
X is selected from C1-4 alkylene, xe2x80x94CR2(CR2R2b)(CH2)txe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR1xe2x80x3)xe2x80x94, xe2x80x94CR2(NR1xe2x80x3R2)xe2x80x94, xe2x80x94CR2(OR2)xe2x80x94, xe2x80x94CR2(SR2)xe2x80x94, xe2x80x94C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O), xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR2R2axe2x80x94, xe2x80x94CR2R2aS(O)pxe2x80x94, xe2x80x94S(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2xe2x80x94, xe2x80x94NR2S(O)2CR2R2axe2x80x94, xe2x80x94CR2R2aS(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2NR2xe2x80x94, xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, xe2x80x94NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)Oxe2x80x94, xe2x80x94OC(O)NR2xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2CR2R2axe2x80x94, xe2x80x94CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and xe2x80x94OCR2R2axe2x80x94;
Y is selected from:
CH2NR2R2a;
CH2CH2NR2R2a;
C3-10 carbocyclic residue substituted with 0-2 R4a, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, C(xe2x95x90NR2)NR2R2a, C(xe2x95x90NS(O)2R5)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, C(O)NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, N(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R4a, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, (CH2)rxe2x80x94F, (CH2)rxe2x80x94Br, (CH2)rxe2x80x94Cl, Cl, Br, F, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, (CH2)rNxe2x95x90CHOR3, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, C(xe2x95x90NR2)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2C1-4 alkyl, C(O)NHSO2C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;
R4b, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, C(xe2x95x90NR3)NR3R3a, NR3C(xe2x95x90NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)pxe2x80x94C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl,
alternatively, R7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
n, at each occurrence, is selected from 0, 1, 2, and 3;
m, at each occurrence, is selected from 0, 1, and 2;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
s, at each occurrence, is selected from 0, 1, and 2; and,
t, at each occurrence, is selected from 0, 1, 2, and 3.
[9] In a preferred embodiment, the present invention provides a novel compound, wherein the compound is selected from the group: 
wherein compounds of the above formulas are substituted with 0-2 R3;
G is selected from the group: 
xe2x80x83A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
B is selected from: H, Y, Xxe2x80x94Y;
X is selected from C1-4 alkylene, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR)xe2x80x94, xe2x80x94CR2(NR2R2a)xe2x80x94, xe2x80x94C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O), xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, xe2x80x94NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2CR2R2axe2x80x94, xe2x80x94CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and xe2x80x94OCR2R2axe2x80x94;
Y is CH2NR2R2a or CH2CH2NR2R2a;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
alternatively, Y is selected from the following bicyclic heteroaryl ring systems: 
xe2x80x83K is selected from O, S, NH, and N; and,
s is 0.
[10] In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
[11] In another embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with I or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Alkenylxe2x80x9d is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 Alkynyl is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc. . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. Preferred prodrugs are amidine prodrugs wherein D is C(xe2x95x90NR7)NH2 or its tautomer C(xe2x95x90NH)NHR7 and R7 is selected from OH, C1-4 alkoxy, C6-10 aryloxy, C1-4 alkoxycarbonyl, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, and C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl. More preferred prodrugs are where R7 is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit factor Xa. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect (in this case, inhibition of factor Xa) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.
The compounds of the present invention represented by Formula I consist of a group xe2x80x9cDxe2x80x94Exe2x80x94Gxe2x80x94(CH2)sxe2x80x94xe2x80x9d and a group xe2x80x9cxe2x80x94Axe2x80x94Bxe2x80x9d attached to a [5,6]- or [5,7]-heterobicyclic core structure of varying composition. The five-membered ring can be pyrazole, triazole, isoxazole or isothiazole and this ring can be fused to a variety of six- or seven membered rings including but not limited to piperidinone, pyridinone, pyrimidinone, pyrimidinedione, pyranone, diazepinone, diazepinedione. The following discussion and schemes will describe methods for the syntheses of the heterobicyclic cores and attachment to the groups xe2x80x9cGxe2x80x94(CH2)sxe2x80x94xe2x80x9d and xe2x80x9cxe2x80x94Axe2x80x94Bxe2x80x9d.
The 4-aminopyrazole-5-carboxylate V is a useful intermediate for the preparation of many of the pyrazole fused compounds of Formula I wherein the xe2x80x9cGxe2x80x94(CH2)5xe2x80x94xe2x80x9d residue is attached to a nitrogen atom of the pyrazole (Scheme I). This intermediate can be prepared in a variety of ways from hydrazines I. Hydrazines I are readily available starting materials. Aromatic hydrazines (G is aryl, s=0) are conveniently prepared from the corresponding aniline by diazotization with NaNO2 in acidic media followed by reduction of the resulting diazonium ion with a suitable reducing agent, with SnCl2 being a preferred reagent. Non-aromatic hydrazines represented by I are readily prepared by a variety of methods, such as by displacement of a suitable halogen compound with hydrazine or with a protected hydrazine followed by deprotection. Condensation of hydrazines I with a suitable hemiacetal or aldehyde followed by halogenation with NBS or NCS leads to hydrazidoyl halides II. Alternatively, the hydrazines I can be acylated with an acid chloride and converted to hydrazidoyl halides II by carbon tetrahalide/triphenylphosphine. The hydrazidoyl halides II are versatile intermediates for pyrazole synthesis (Shawali, A. S.; et. al. J. Het. Chem. 1980, 17, 833). The halide can be displaced with cyanide ion to afford cyanide III. Cyano compounds of this type (where G is aryl and s=0) can also be prepared more directly by diazotization of aniline IV followed by direct reaction with a cyano-containing active methylene compound, where R1a can include a variety of groups such as ester, ketone, cyano, trifluoromethyl, sulfone, aryl, etc. (Butler, R. N.; et. al. J. Chem. Soc. Chem. Commun. 1992, 20, 1481). Treatment of III with a bromoacetate in the presence of a suitable base such as carbonate or trialkylamine results in N-alkylation followed by ring closure to give the 4-aminopyrazole-5-carboxylate V. Alternatively, treatment of II with a nitropyruvate in the presence of a base such as alkoxide provides a 4-nitropyrazole by displacement of the halide followed by ring closure of the nitrogen onto the carbonyl group. Reduction of the nitro group can be accomplished by a variety of reducing agents, a preferred one of which is SnCl2, to give the 4-aminopyrazole-5-carboxylate V. The hyrazidoyl halide II can also be reacted with a ketoester where Rxe2x80x2 represents a masked ester, preferably a 2-furyl residue, to give a pyrazole-4-carboxylate VI. Ester hydrolysis, conversion to an acyl azide, either via the acid chloride or anhydride, heating to generate an isocyanate via Curtius rearrangement, and finally treatment with water affords the 4-aminopyrazole VII. Alternatively, the amino can be masked as an appropriate carbamate by using an alcohol instead of water in the Curtius rearrangement. When Rxe2x80x2=2-furyl, the furan can be oxidatively cleaved under a variety of conditions, such as sodium periodate with catalytic ruthenium trichloride, or KMnO4, to afford a carboxylic acid which can be esterified to afford the 4-aminopyrazole-5-carboxylate V.
Another route to the 4-aminopyrazole V involves condensation of the hydrazine I with an appropriate diketone or monoprotected diketone to form a 3,5-disubstituted pyrazole in which the 5-substituent is a carboxylic ester. With proper choice of the G group, this pyrazole can be selectively nitrated at the 4-position with nitrating agents such as nitric acid or ammonium nitrate/trifluoroacetic anhydride. Reduction of the nitro group under a variety of conditions, such as with tin (II) chloride or catalytic hydrogenation, affords the 4-aminopyrazole V. This route can also be carried out using a diketone with a 2-furyl group as a latent carboxylate, giving initially a 3,5-disubstituted pyrazole in which the 5-substituent is the 2-furyl group. Oxidative cleavage of the furyl group to a carboxylate, nitration of the pyrazole 4-position, esterification and nitro reduction then affords 4-aminopyrazole V. It will be recognized by those skilled in the art that the synthetic route chosen to V will depend on additional functionality present in the molecule of interest and the route may require additional protection/deprotection sequences as well as modifications in the order of synthetic steps. 
In Scheme II is shown how the 4-aminopyrazole-5-carboxylate V can be utilized to prepare a variety of structures described by Formula I where the Axe2x80x94B residue is connected to a nitrogen atom of the bicyclic core. The 4-amino group can be protected as a suitable carbamate (see Greene and Wuts, Protective Groups in Organic Synthesis, Wiley and Sons, 1991) or as an azide group (NaNO2, acid, NaN3). In some cases it may not be necessary to protect the amino functionality, as will be recognized by those skilled in the art. Unmasking of the ester residue involves either basic hydrolysis (R=Me, Et), hydrogenolysis (R=Bn) or trifluoroacetic acid (R=t-Bu). Coupling of the resulting acid with the appropriate amine H2Nxe2x80x94Axe2x80x94B can be accomplished by a wide variety of methods known to those skilled in the art, including dicyclohexylcarbodiimide and N,N-dimethylaminopyridine, the mixed anhydride method, the BOP reagent, and many others. Alternatively, the amide bond can be formed directly from the ester (R=Me, Et) by reacting the ester with an aluminum reagent prepared from the amine H2Nxe2x80x94Axe2x80x94B and trimethylaluminum. Deprotection of the amino group, if required, provides compounds VIII. Treating this amino amide with carbonyl diimidazole or other phosgene equivalent, such as triphosgene, provides pyrazolopyrimidinediones IX. Alternatively, aminocarboxylate V can be converted to pyrazolopyrimidinediones IX in a single step by heating with an appropriate isocyanate OCNxe2x80x94Axe2x80x94B in the presence of a base such as sodium hydride. Treating VIII with a substituted bromoacetyl chloride or bromide in the presence of a base such as triethylamine affords the pyrazolodiazepinediones X. Refluxing VIII in the presence of formic acid provides the pyrazolopyrimidinones XI (R3=H). Substituted derivatives XI can be obtained by refluxing VIII in the presence of triethylorthoacetate (R3=Me) or other orthoesters. Reduction of XI with catalytic hydrogenation, sodium borohydride in acidic medium or other reducing agent can provide compounds of type XII. Additionally, V can be treated with a bromoacetate in the presence of a base such as carbonate or sodium hydride to provide XIII. Selective hydrolysis of either ester of XIII followed by standard coupling with H2Nxe2x80x94Axe2x80x94B and subsequent heating affords compounds XIV, which are regioisomeric with X. Oxygen analogs of XIV are prepared by converting the amino group of V to a hydroxy group via a diazonium ion. Coupling with the amine H2Nxe2x80x94Axe2x80x94B by any of a wide variety of procedures yields XV. O-alkylation of XV with a bromoacetate in the presence of a base such as sodium hydride leads to XVI, the oxygen analogs of XIV. In the cases of compounds IX, X, XII and XIV the nitrogen atom can be further functionalized to provide additional analogs, such as by treating with methyl iodide in the presence of a base to afford the N-methyl derivatives. 
The 4-aminopyrazole-5-carboxylate can be used to prepare pyrazolopyranone and pyrazolopyridinone derivatives, in which the Axe2x80x94B residue is attached to a carbon atom of the bicyclic core, as shown in Scheme III. N-protection of V as described previously can be followed by straightforward conversion of the ester residue to an acid chloride. Treatment of this acid chloride with a zinc cuprate reagent derived from Brxe2x80x94CH2xe2x80x94Axe2x80x94B (A=aryl) will afford the ketone XVII after N-deprotection. fleating XVII with dimethylformamide dimethylacetal or with an orthoester can provide the pyrazolopyridinone compounds XVIII. Conversion of the 4-amino residue of XVII to a hydroxyl group via the diazonium ion will lead to XIX, which will provide the pyrazolopyranone derivatives XX under similar cyclization conditions. Alternatively, treatment of the acid chloride XXI, obtained as described above where N-PG can represent a carbamate protected nitrogen or can represent conversion of the amino group to an azide group as described previously, with a suitable enamine in the presence of a base such as triethylamine can afford the ketone XXII. N-deprotection followed by heating will afford the pyrazolopyridinones XXIII (XVIII where R3=H). Also, the ketone XVII can be prepared from the cyano compound III by treatment with a suitable bromoketone in the presence of a base such as carbonate or triethylamine. The required bromoketone is readily available by treating an appropriate acid chloride with diazomethane followed by HBr. It will be recognized by those skilled in the art that the syntheses of the compounds described in Scheme III may require additional protection/deprotection steps or modifications in the order of carrying out the steps, depending on additional functionality present in the compounds of interest. 
Additional oxygen-containing bicyclic systems can be prepared as shown in Scheme IV. The 4-amino-5-carboxylate V can be converted to its 4-hydroxy derivative via the diazonium ion to give XXIV. Ester deprotection and amide bond formation with an appropriate H2Nxe2x80x94Axe2x80x94B as described in Scheme II will afford the amide XXV. Alternatively, the amide bond can be formed directly from the ester by addition of the aluminum reagent derived from H2Nxe2x80x94Axe2x80x94B and trimetbylaluminum. The 4-hydroxy substituent can be easily protected if required by any of a number of protecting groups, such as with t-butyldimethylsilyl ether (TBS), and then deprotected following amide bond formation. Treating the hydroxy amide XXV with carbonyl diimidazole or other phosgene equivalent, such as triphosgene, can provide the bicyclic core XXVI. Heating XXV in the presence of paraformaldehyde in the presence of a suitable acid such as p-toluenesulfonic acid will provide XXVII (R3=H). Alternatively, XXV can be treated with dibromomethane in the presence of a suitable base such as carbonate to afford XXVII (R3=H). Other aldehydes and substituted dibromomethanes can provide substituted derivatives of XXVII where R3 is not hydrogen. 
Additional bicyclic systems in which the Axe2x80x94B residue is substituted on a carbon atom can be prepared as shown in Scheme V. N-protection of 4-aminopyrazole-5-carboxylate V can be followed by manipulation of the ester to afford an acid chloride or an N-methoxy-N-methyl amide. Addition of an enolate derived from RO2CCH2xe2x80x94Axe2x80x94B and a base such as lithium duisopropylamide or lithium hexamethyldisilazide provides XXVIII. The N-methoxy-N-methyl amide is the preferred reaction partner for this addition, as this functionality prevents the formation of overaddition products. Alternatively, the enolate addition reaction could be done on the ester as well. N-deprotection of the 4-amino substituent allows it to close onto the ester residue and provides the pyrazolopiperidinedione XXIX. Manipulation of the ester residue of XXVIII can lead to XXX where X represents a suitable leaving group such as a bromide or mesylate residue. A variety of methods can be utilized for the transformation of XXVIII to XXX, such as ketone protection, reduction of the ester to a primary alcohol, ketone deprotection and conversion of the primary alcohol to a bromide using CBr4/PPh3 or to a mesylate using methanesulfonyl chloride and a base such as triethylamine. Alternatively, the ester can be hydrolyzed to the acid that can be reduced to the primary alcohol with borane and converted to a leaving group as just described. N-deprotection liberates the 4-amino group, which provides compounds of structure XXXI upon heating or treatment with base. The corresponding oxygen derivative is also available from XXVIII. N-deprotection, diazotization with NaNO2 in acidic medium and treatment with sulfuric acid produces the 4-hydroxy derivative XXXII. Protection of the alcohol functionality, for example as the TBS ether, followed by ester manipulation as described above and subsequent alcohol deprotection, produces XXXIII. Treatment of XXXIII with a suitable base such as carbonate leads to ring closure to afford compounds XXXIV. Alternatively, compounds XXXIII where Xxe2x95x90OH can be closed to XXXIV via a Mitsunobu reaction by treatment with diethylazodicarboxylate and triphenylphosphine.
In scheme VI is shown how to make additional bicyclic systems in which the Axe2x80x94B residue is substituted on a carbon atom and the ring is substituted with an R3 group. Ester XXVIII can be converted under standard conditions to the N-methoxy-N-methyl amide XXXV. Addition of an appropriate Grignard reagent R3MgBr produces a ketone, which upon N-deprotection and heating in acidic conditions leads to the substituted pyridones XXXVI. Hydride reduction, with REDAL for example, will produce the piperidone XXXVII. Alternatively, diisobutylaluminum hydride reduction of the N-methoxy-N-methyl amide gives an aldehyde which will add a suitable Grignard reagent R3MgBr to afford XXXVIII. Conversion of the alcohol to a leaving group, for example by making the mesylate with methanesulfonyl chloride and a trialkylamine base, followed by N-deprotection leads to ring closure to piperidones XXXVII. The alcohol XXXVIII can also be prepared from enamine XXII from Scheme III by hydrolysis to the corresponding aldehyde followed by addition of the appropriate Grignard reagent R3MgBr. 
Preparation of a bicyclic system containing a seven-membered ring in which the Axe2x80x94B residue is attached to a carbon atom is described in Scheme VII. N-protection of aminoketone XVII, where N-PG represents preferably an N-protected nitrogen wherein both Nxe2x80x94H groups are masked, such as by conversion to an azide group, is followed by formation of a ketone enolate, with a base such as lithium diisopropylamide, and reaction with a bromoacetate to afford XXXIX. N-deprotection followed by heating of the resulting amino ester affords XL. Alternatively, the ester can be converted by straightforward means to a more reactive species prior to ring closure, such as a mixed anhydride or acid chloride. Treatment of XVII with bromoacetyl bromide and a base such as triethylamine gives the acylamine XLI that can be cyclized by formation of the ketone enolate with a base such as lithium diisopropylamide. 
Additional seven-membered ring-containing bicyclic systems can be prepared as shown in Scheme VIII. The hydrazidoyl halide II, prepared as shown in Scheme I, can be cyclized with a cyanopyruvate in the presence of a base such as alkoxide to afford 4-cyanopyrazole XLII. Ester deprotection and coupling with H2Nxe2x80x94Axe2x80x94B as described in previous schemes yields cyanoamide XLIII. Reduction of the nitrile can be accomplished by various methods, such as by catalytic hydrogenation or by reduction with sodium borohydride in the presence of cobalt chloride. Cyclization of the resulting aminoamide using carbonyl diimidazole or other phosgene equivalent as described previously affords compounds XLIV. For the corresponding compound wherein the Axe2x80x94B residue is attached to carbon, the ester XLII can be converted to the N-methoxy-N-methyl amide as described previously. Treatment of this amide with the enolate derived from RO2CH2Axe2x80x94B yields the ketone XLV. Catalytic hydrogenation of the nitrile affords an amine that upon heating undergoes cyclization to afford XLVI. The oxygen containing analog corresponding to XLIV is obtained from ester VI, prepared as described in Scheme I. The group Rxe2x80x2 represents preferably a 2-furyl residue as a masked carboxylic acid. Reduction of the ester group of VI with a hydride reducing agent such as diisobutylaluminum hydride is followed by protection of the resulting primary alcohol, such as by a TBS ether. When Rxe2x80x2 is 2-furyl, the carboxylic acid can be unmasked by oxidation by a variety of reagents, including ozone, potassium permanganate, and sodium periodate in the presence of ruthenium trichloride. Coupling with a suitable with H2Nxe2x80x94Axe2x80x94B as described in previous schemes yields the amide XLVII. Deprotection of the alcohol affords a hydroxy amide, which can be cyclized using carbonyl diimidazole as described previously to afford compounds XLVIII. 
Bicyclic compounds of Formula I containing a carbon atom at the pyrazole 4-position are prepared by a [3+2] cycloaddition strategy as shown in Scheme IX (for a review of [3+2] cycloadditions, see 1,3-Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, N.Y., 1984). 
Treatment of unsaturated lactone XLIX, which is readily available by standard procedures known to those skilled in the art, with an aluminum reagent prepared from an appropriate amine H2Nxe2x80x94Axe2x80x94B and trimethylaluminum affords the ring-opened amide L. Conversion of the primary alcohol under standard conditions to a suitable leaving group, such as a bromide or mesylate, and subjection to basic conditions affords the required unsaturated lactam LI. Treatment of hydrazidoyl halide II, prepared as shown in Scheme I where X=Cl or Br, with triethylamine generates a 1,3-dipolar intermediate LII, which can undergo a [3+2] cycloaddition with the olefin LI to produce the bicyclic pyrazolidine LIII as the predominant regioisomer. Mild oxidation with reagents such as chloranil or nickel peroxide will produce the pyrazolopiperidones LIV. Further oxidation, such as with DDQ, can produce the unsaturated derivatives LV. These steps can be reversed such that initial complete oxidation to LV can be followed by reduction, such as by catalytic hydrogenation, to produce LIV. The ketone derivatives can be prepared by condensation of an appropriate amine H2Nxe2x80x94Axe2x80x94B with the cyclic anhydride LVI to give LVII. Alternatively, a saturated derivative of LVI can be condensed with an appropriate amine H2Nxe2x80x94Axe2x80x94B followed by oxidation to the unsaturated derivative LVII, such as by treatment with LDA/PhSeSePh and subsequent oxidative selenoxide elimination. The olefin LVII undergoes similar [3+2] cycloaddition to give a pyrazolidine intermediate that is readily oxidized to the pyrazolopiperidinedione derivatives LVIII by a variety of oxidizing agents.
An alternative preparation of compound LIV is also described. A standard alkylation/acylation sequence on the amine H2Nxe2x80x94Axe2x80x94B affords amide ester LIX, which contains a protected ketone functionality. A variety of reaction conditions can be employed for these transformations, which are known to those skilled in the art. Deprotection of the ketone followed by Dieckmann condensation under basic conditions affords the cyclic diketoamides LX. Condensation of LX with an appropriate hydrazine is readily accomplished by heating in a solvent such as acetic acid or ethanol to afford the previously described LIV.
Pyrazolopiperidone compounds LXVI (where n=1) wherein the pyrazole 4-substituent R1a is a trifluoromethyl group can be prepared via the method outlined in Scheme X. Coupling of the acid LXI with amines H2Nxe2x80x94Axe2x80x94B can be accomplished under a variety of conditions, such as via the acid chloride, giving amide LXII. A straightforward sequence involving cleavage of the tetrahydrofuran ring and intramolecular cyclization on the amide nitrogen affords the ketolactam LXIII. This compound can also be prepared from the lactam LXIV by introduction of sulfur substituents and subsequent oxidation to the ketolactam LXIII. Formation of the morpholine or related enamine followed by reaction with trifluoroacetic anhydride leads to the trifluoroacetylated intermediate LXV. Alternatively, dichlorination of lactam LXIV with PCl5 or analogous reagents, heating with excess morpholine or related amine, and reacting the enamine derived in this way with trifluoroacetic anhydride also yields the trifluoroacetylated intermediate LXV. This compound can be readily condensed with an appropriate hydrazine to afford the pyrazolopiperidone compounds LXVI. Analogous chemistry can be utilized to afford [5,7]-fused ring systems (where n=2).
Unsaturated analogs of the above compounds can be prepared as shown in the bottom of Scheme X. Bromination of LXVII, prepared as described in Scheme IX and the top of Scheme X, affords bromo analog LXVIII. Elimination of HBr by treatment with any of a variety of bases, such as DBU, will afford the unsaturated bicylic analogs LXIX. Additional analogs can be prepared by displacement of the bromide LXVIII by any of a wide variety of nitrogen-, oxygen- and sulfur-based nucleophiles. 
Additional [5,7]-fused bicyclic systems which contain an additional heteroatom in the seven-membered ring can be prepared as shown in Scheme XI. Compounds LXXI where X is O or S can be prepared from commercially available tetrahydro-4H-pyran-4-one and tetrahydrothiopyran-4-one. Photoinduced Schmidt rearrangement of (triisopropylsilyl)azidohydrin (Evans, P. A. and Modi, D. P. J. Org. Chem. 1995, 60, 6662-6663), which is formed from tetrahydro-4H-pyran-4-one and tetrahydrothiopyran-4-one, provides tetrahydro-1,4-oxazepin-5(2H)-one and tetrahydro-1,4-thiazepin-5(2H)-one. Compounds LXXI where X is NH or NR can be prepared by Schmidt rearrangement of 4-piperidone monohydrate hydrochloride or protected 4-piperidone (Groves, J. T. and Chambers, R. R. Jr. J. Am. Chem. Soc. 1984, 106, 630-638). Ullmann coupling of the lactam with I(Br)xe2x80x94Axe2x80x94B provides the lactam LXXII with an Axe2x80x94B residue. Dichloronation with phosphorus pentachloride or related reagent affords a dichlorinated intermediate which can react with morpholine to give the enamine LXXIII. Reaction of LXXIII with DMAP and an appropriate acid chloride or acid anhydride provides the acylenamine intermediate LXXIV which can be condensed with an appropriate hydrazine in acetic acid to afford the [5,7]-fused bicyclic compounds LXXV. 
Bicyclic compounds of Formula I which contain a carbon atom at the pyrazole 4-position and wherein the Axe2x80x94B residue is attached to a carbon atom are also prepared by a [3+2] cycloaddition strategy as shown in Scheme XII. Unsaturated cyclic ketones LXXVI are readily available by standard synthetic methods known to those skilled in the art. The [3+2] cycloaddition with the 1,3-dipole generated from II as described previously gives a pyrazolidine intermediate that can be readily oxidized to the pyrazolocyclohexanone LXXVII. Introduction of a double bond, such as by treating with LDA and PhSeSePh followed by oxidative selenoxide elimination, gives the unsaturated derivative LXXVIII. Incorporation of a residue such as a protected alcohol into the unsaturated ketone, represented by LXXIX, leads to pyrazolocyclohexanone LXXX following [3+2] cycloaddition and subsequent oxidation. Deprotection of the alcohol and oxidation by a variety of reagents affords the pyrazolocyclohexanedione LXXXI. 
Additional bicyclic compounds of Formula I containing a carbon atom at the pyrazole 4-position are described in Scheme XIII. Condensation of hydrazidoyl halide II with a diketoester in the presence of a base such as alkoxide affords pyrazoles LXXXII. Heating this ketoester in the presence of readily available hydrazines Axe2x80x94Bxe2x80x94NHNH2 affords the pyrazolopyridazinones LXXXIII. For preparation of pyrazolopyridazinones where R3 is hydrogen, the hydrazidoyl halide II can be cyclized with a furyl ketoester in the presence of alkoxide base to afford LXXXIV. Standard functional group manipulations, involving ester reduction and protection, furyl oxidation and esterification leads to LXXXV, although not necessarily in that order. Those skilled in the art will be able to determine a proper order and appropriate reagents for achieving these transformations. Alcohol deprotection and oxidation, such as by manganese dioxide, affords an aldehyde ester which readily produces LXXXVI upon heating in the presence of a hydrazine Axe2x80x94Bxe2x80x94NHNH2. Appropriate functional group manipulation of LXXXIV, of which many methods are available, can also afford ester acids LXXXVII. Activation of the carboxylic acid, such as by formation of the acid chloride with oxalyl chloride, followed by heating in the presence of a hydrazine Axe2x80x94Bxe2x80x94NHNH2 affords the pyrazolopyridazinedione LXXXVIII. 
The preparation of the compounds of Formula I where the five-membered ring is triazole is accomplished using azide intermediates. Azides readily undergo [3+2] cycloaddition reactions with a variety of olefins and alkynes, and the application of this reaction to the synthesis of the triazole-fused bicyclic compounds of Formula I is shown in Scheme XIV. As described for the pyrazole-fused compounds previously, the 4-amino-1,2,3-triazole-5-carboxylate XCII is a particularly useful intermediate for the preparation of many of the triazole-fused bicyclic systems. The required azides LXXXIX are readily available. Aliphatic azides are easily prepared from the corresponding bromide by displacement with sodium azide in solvents such as dimethylformamide and dimethyl sulfoxide. Where xe2x80x9cGxe2x80x94(CH2)sxe2x80x94xe2x80x9d represents an aryl azide (G is aryl, s=0), the azides are readily available from the corresponding aniline by diazotization with NaNO2 in acidic medium followed by displacement of the diazonium ion with sodium azide. The [3+2] cycloaddition of azides LXXXIX with nitroolefins XC (Rxe2x80x2=Me, 2-furyl) affords the triazoles XCI as the major product, in which initial cyclization to a triazoline intermediate is followed by autooxidation to the triazole products (Cailleux, P.; et. al. Bull. Soc. Chim. Belg. 1996, 105, 45). These reactions can be performed in refluxing benzene or similar solvents at similar temperatures. Conversion of XCI to the 4-amino-1,2,3-triazole-5-carboxylate XCII is straightforward. When Rxe2x80x2 is methyl, oxidation of the methyl group with an oxidant such as KMnO4 gives the carboxylic acid which can be esterified to an appropriate ester. Reduction of the nitro group by any of a variety of reducing agents, preferably SnCl2 or catalytic hydrogenation, gives XCII. When Rxe2x80x2 is 2-furyl, the carboxylic acid can be unmasked by a variety of oxidizing agents, including ozone, KMnO4 and sodium periodate/ruthenium trichloride, to give the carboxylic acid which can be esterified and reduced as described above to afford XCII. The 4-hydroxy-1,2,3-triazole-5-carboxylates can be obtained via the diazonium ion of XCII as described for the pyrazole series to afford XCIV.
The reaction of azides LXXXIX with active methylene compounds is also illustrated in Scheme XIV. Treating LXXXIX with cyano- or nitropyruvates in the presence of a base such as alkoxide affords triazoles XCIII. The triazole-4-carboxylate derivatives can be prepared by treating LXXXIX with a furyl ketoester in the presence of alkoxide base to afford XCV. These reactions are analogous to those described in Scheme I for the pyrazole derivatives. The triazole-containing bicyclic systems having a carbon atom at the 4-position of the triazole can be prepared by [3+2] cycloaddition of an appropriate azide LXXXIX with an unsaturated lactam LI or an unsaturated cyclic ketone LXXVI. These cycloadditions are performed by heating in an appropriate solvent, such as benzene or toluene. The resulting triazoline intermediates are readily oxidized to the fused triazoles using chloroanil, nickel peroxide or other mild oxidant to give XCVI and XCVII, respectively. The triazole intermediates XCI, XCII, XCIII, XCIV, XCV, XCVI and XCVII can be transformed into the final triazole-containing bicyclic compounds described by Formula I following the procedures described for the corresponding pyrazole derivatives in Schemes II-XI. The nitro group present in XCI and XCIII can correspond to the xe2x80x9cN-PGxe2x80x9d residue described in Schemes II-VIII, or alternatively, the nitro group can be reduced at an appropriate time and further protected as a suitable carbamate derivative or as an azido group. 
The preparation of the compounds of Formula I where the five-membered ring is isoxazole is accomplished as shown in Scheme XV. The hydroximinoyl chloride XCIX is a useful intermediate for the preparation of isoxazole-fused compounds. This intermediate is readily available from appropriate aldehydes XCVIII by oxime formation with hydroxylamine followed by chlorination with N-chlorosuccinimide. Treatment of XCIX with a cyanoacetate in the presence of a base such as carbonate results in cyclization to give a 5-aminoisoxazole-4-carboxylate C. The amino residue of C can be readily converted into the corresponding hydroxy or cyano derivatives CI and CII, respectively, via the diazonium ion, as described earlier for the pyrazole and triazole compounds.
The isoxazole-5-carboxylates are available from cyclization of XCIX with a furan ketoester to give CIII. Oxidation of the furan to a carboxylic acid residue is accomplished by a variety of oxidizing agents as described earlier.
The hydroxyiminoyl chloride XCIX can also be treated with a base such as triethylamine to generate a nitrile oxide intermediate, which can undergo [3+2] cycloaddition reactions with appropriate olefins or alkynes. This is a convenient method by which to prepare bicyclic compounds containing a carbon atom at the 5-position of the isoxazole ring. For example, cycloaddition with the unsaturated lactam LI leads to formation of a fused isoxazoline intermediate which is readily oxidized with reagents such as nickel peroxide, chloranil or DDQ to afford CIV. Cycloaddition with unsaturated cyclic ketone and oxidation under the same conditions affords the ketone analog CV. The isoxazole-fused intermediates C, CI, CII, CIII, CIV and CV can be transformed into the final isoxazole-containing bicyclic compounds described by Formula I following the procedures described for the corresponding pyrazole derivatives in Schemes II-XI. 
The preparation of the compounds of Formula I where the five-membered ring is isothiazole is accomplished as shown in Scheme XVI. One method for preparing the 5-aminoisothiazole-4-carboxylate intermediate CVIII proceeds from readily available acid chloride CVI. Condensation of CVI with a cyanoacetate in the presence of a base such as a magnesium alkoxide followed by treatment with ammonia in an alcoholic solvent gives an aminonitrile CVII. Treatment with hydrogen sulfide in the presence of a base such as triethylamine affords a thioamide that can undergo an oxidative cyclization to CVIII upon treatment with hydrogen peroxide or bromine. As described in previous schemes, the amino residue can easily be converted into the corresponding hydroxyl or cyano derivatives CIX or CX, respectively.
Another useful intermediate for the preparation of isothiazole compounds of the present invention is the nitrile sulfide CXIII. This intermediate can be generated conveniently from heterocycle CXII, which itself can be prepared from amides CXI either by treating with chlorocarbonylsulfenyl chloride or by treating with trichloromethanesulfenyl chloride followed by aqueous sodium hydroxide. Thermolysis of heterocycle CXII affords the nitrile sulfide CXIII, which can undergo many of the same reactions as the corresponding nitrile oxide intermediates. For example, [3+2] cycloaddition of CXIII with olefins LI and LXXVI can afford, after subsequent mild oxidation as described previously, the isothiazole-fused compounds CXIV and CXV, respectively. Isothiazole intermediates CVIII, CIX, CX, CXIV and CXV can be transformed into the final isothiazole-containing bicyclic compounds described by Formula I following the procedures described for the corresponding pyrazole derivatives in Schemes II-XI. 
Formula I also describes pyrazole-fused bicyclic compounds in which the xe2x80x9cGxe2x80x94(CH2)sxe2x80x94xe2x80x9d group resides on a carbon atom of the pyrazole ring,. These compounds can be prepared as shown in Scheme XVII. Condensation of acid chlorides CVI with cyanoacetates in the presence of a base such as magnesium methoxide affords an enol derivative that is converted to the enol ether CXVI (Xxe2x95x90OMe) with diazomethane or to the chloro derivative CXVI (Xxe2x95x90Cl) with POCl3. Heating with hydrazine (Rxe2x80x2xe2x95x90H) or a substituted hydrazine affords 5-amino-4-carboxylate CXVII. The amino residue of CXVII can be converted to the hydroxyl or cyano derivative CXVIII or CXIX, respectively via the diazonium ion as described previously.
The 5-carboxylate derivatives can be prepared by condensing a substituted hydrazine with a hemiacetal or related derivative represented by CXX. Chlorination or bromination with NCS or NBS, respectively, affords the hydrazidoyl halides CXXI. Reaction of CXXI with the anion of a furyl ketoester affords the 5-carboxylate CXXII, the furan residue of which can be oxidized to a carboxylic acid residue by methods described previously.
The hydrazidoyl halides CXXI can also participate in [3+2] cycloadditions as described previously to afford, after oxidation of the intermediate pyrazolines, the pyrazole-fused compounds CXXIII and CXXIV. The intermediates CXVII, CXVIII, CXIX, CXXII, CXXIII and CXXIV can be transformed into the final C-linked pyrazole-containing bicyclic compounds described by Formula I following the procedures described for the corresponding N-linked pyrazole derivatives in Schemes II-XI. 
Bicyclic compounds of the present invention in which the five membered ring is pyrrole and the G-containing group is attached to a carbon atom can be prepared as shown in Scheme XVIII. For compounds of this type wherein a nitrogen atom is required at the pyrrolo 2-position, the 2-aminopyrrole CXXVI is a useful intermediate. This compound can be prepared by condensation of readily obtained aminocarbonyl compounds CXXV with an appropriate cyanoacetate. This condensation can be carried out under basic conditions or by heating with azeotropic removal of water. The 2-aminopyrroles CXXVI can be diazotized and subsequently converted into the 2-cyano- and 2-hydroxypyrroles CXXVII, which are suitable intermediates for a variety of the bicyclic compounds of this invention. Pyrrole 2,3-dicarboxylates can also be prepared from aminocarbonyl compounds CXXV. Michael addition under basic conditions with acetylenedicarboxylate esters is followed by in situ ring closure to afford the pyrrole 2,3-dicarboxylate diester. Selective hydrolysis of one of the esters, typically the 2-ester, affords the pyrrole 2-carboxylic acid CXXIII. Curtius rearrangement of CXXIII affords another route to the 2-aminopyrrole CXXVI. Also, the carboxylic acid can be reduced to the alcohol CXXIX using borane or by sodium borohydride reduction of the derived mixed anhydride. Following procedures described in Schemes II-VIII and Scheme XIII, the intermediates CXXVI, CXXVII, CXXIII and CXXIX can be converted to the final pyrrolo-fused bicyclic compounds of Formula I. Other procedures not described here are also known to those skilled in the art and can be used to prepare the pyrrolo-fused bicyclic compounds of Formula I. 
Bicyclic compounds of the present invention in which the five membered ring is furan and the G-containing group is attached to a carbon atom can be prepared as shown in Scheme XIX. For compounds of this type wherein a nitrogen atom is required at the furyl 2-position, the 2-aminofuran CXXXI is a useful intermediate. These compounds can be prepared analogously to the pyrrole analogs described in Scheme XVIII. Thus, condensation of readily obtained hydroxycarbonyl compounds CXXX with an appropriate cyanoacetate affords the 2-aminofurans CXXXI. This condensation can be carried out under basic conditions or by heating with azeotropic removal of water. The 2-aminofurans CXXXI can be diazotized and subsequently converted into the 2-cyano- and 2-hydroxyfurans CXXXII, which are suitable intermediates for a variety of the bicyclic compounds of this invention. Furan 2,3-dicarboxylates can also be prepared from hydroxycarbonyl compounds CXXX, analogously to the pyrrole analogs described in Scheme XVIII. Michael addition of CXXX under basic conditions with acetylenedicarboxylate esters is followed by in situ ring closure to afford the furan 2,3-dicarboxylate diester. Selective hydrolysis of one of the esters, typically the 2-ester, affords the furan 2-carboxylic acid CXXXIII. Curtius rearrangement of CXXXIII affords another route to the 2-aminofurans CXXXI. Also, the carboxylic acid can be reduced to the alcohol CXXXIV using borane or by sodium borohydride reduction of the derived mixed anhydride. Following procedures described in Schemes II-VIII and Scheme XIII, the intermediates CXXXI, CXXXII, CXXXIII and CXXXIV can be converted to the final furan-fused bicyclic compounds of Formula I. Other procedures not described here are also known to those skilled in the art and can be used to prepare the furan-fused bicyclic compounds of Formula I. 
Bicyclic compounds of the present invention in which the five membered ring is thiophene and the G-containing group is attached to a carbon atom can be prepared as shown in Scheme XX. For compounds of this type wherein a nitrogen atom is required at the thiophene 2-position, the 2-aminothiophene CXXXVI is a useful intermediate. These compounds can be prepared analogously to the pyrrole analogs described in Scheme XVIII. Thus, condensation of readily obtained mercaptocarbonyl compounds CXXXV with an appropriate cyanoacetate affords the 2-aminothiophenes CXXXVI. This condensation can be carried out under basic conditions or by heating with azeotropic removal of water. Alternatively, condensation of the cyanoacetate with ketone CXXXVIII affords olefin CXXXIX. In a subsequent step, CXXXIX can be converted into 2-aminothiophenes CXXXVI by treatment with S8 and a base such as triethylamine. The 2-aminothiophenes CXXXVI can be diazotized and subsequently converted into the 2-cyano- and 2-hydroxythiophenes CXXXVII, which are suitable intermediates for a variety of the bicyclic compounds of this invention. Thiophene 2,3-dicarboxylates can be prepared from alkali-metal acetylenethiolates CXL. These compounds react with acetylenedicarboxylate esters in a [3+2] cycloaddition to afford thiophene 2,3-dicarboxylate diesters. Selective hydrolysis of one of the esters, typically the 2-ester, affords the thiophene 2-carboxylic acid CXLI. Curtius rearrangement of CXLI affords another route to the 2-aminothiophenes CXXXVI. Also, the carboxylic acid can be reduced to the alcohols CXLII using borane or by sodium borohydride reduction of the derived mixed anhydride. Following procedures described in Schemes II-VIII and Scheme XIII, the intermediates CXXXVI, CXXXVII, CXLI and CXLII can be converted to the final thiophene-fused bicyclic compounds of Formula I. Other procedures not described here are also known to those skilled in the art and can be used to prepare the thiophene-fused bicyclic compounds of Formula I. 
Bicyclic compounds of the present invention in which the five membered ring is imidazole and the G-containing group is attached to a nitrogen atom can be prepared as shown in Scheme XXI. These compounds CXLIII through CLXIV, where the R group may be alkyl, aryl or a protecting group PG, are available either from commercial sources or through known prior art and can be represented generically by CLXV. Suitable protection of the imidazole nitrogen affords compounds of the type CLXVI, which are further elaborated via a cupric mediated coupling of appropriate Axe2x80x94B containing boronic acid to yield CLXVII. Subsequent removal of the imidazole-protecting group PG affords compounds such as CLXVIII. The introduction of a substituent G is accomplished as before by the coupling of a G-containing boronic acid in a manner such that the G-group is transferred to the imidazole nitrogen as depicted by CLVIX. 
The Axe2x80x94B moieties can be prepared by methods known to those of skill in the art. The following publications, the contents of which are incorporated herein by reference, describe and exemplify means of preparing Axe2x80x94B moieties: WO97/23212, WO97/30971, WO97/38984, WO98/06694, WO98/01428, WO98/28269, and WO98/28282.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.